Exercise Training And Tetrahydropyridine Regulates Cortical-Associated Learning And Memory

As a healthy lifestyle,exercise training is beneficial for the reduction of a number of neurological disease and dementia across the adult lifespan.Synaptic plasticity has been associated with the development of psychiatric or neurodegenerative diseases in addition to the change of cognitive functions.Numerous studies have reported exercise training increased adult hippocampal neurogenesis and synaptogenesis,however,exercise training affects the cortical synaptic plasticity and cortical-associated learning memory remains unclear.Meanwhile,whether non-motor features of Parkinson's disease,such as cognitive impairment,are related to the alternation of synaptic remodeling and neuronal/dendritic activity is unknown.To answer this questions,we performed multiple of cutting-edge approaches,including two-photon calcium and structure imaging,chemogenetic strategy,behavioral learning or testing.We found:(1)Stressed mice had elevated spine elimination rate in mouse barrel cortex plus deficits in memory retrieval,both of which can be rescued by chronic exercise on treadmill.Exercise also elevated brain-derived neurotrophic factor(BDNF)expression in barrel cortex.The above-mentioned rescuing effects for both spinognesis and memory function were abolished after inhibiting BDNF/tyrosine kinase B(Trk B)pathway.(2)Chronic treadmill exercise activates the mechanistic target of rapamycin(m TOR)pathway in mouse motor cortex.Both ex vivo and in vivo recordings suggest that m TOR activation leads to potentiated postsynaptic excitation and enhanced neuronal activity of layer 5 pyramidal neurons after exercise,in association with improved oligodendrogenesis and axonal myelination.Exercise training also improves dendritic spine formation and motor learning.Together,exercise activates m TOR pathway,which is necessary for spinogenesis,neuronal activation and axonal myelination leading to improved motor learning.(3)A single dose of MPTP in mice led to impaired memory retention on multiple motor learning tasks and in vivo two-photon imaging in the primary motor cortex revealed dendritic spine loss,a substantial increase of NMDA-receptor-dependent calcium spikes in apical tuft dendrites of layer 5 pyramidal neurons,and decreased activity in somatostatin-expressing inhibitory interneurons.Chemogenetic activation of SST-INs reversed MPTP-induced dendritic spine instability and defective Ca MKII autophosphorylation,and enhanced motor skill performance.Together,our findings suggest that cortical disinhibition may contribute to learning and memory deficits in early-stage Parkinson's disease.In summary,we found exercise training significant prevents stress-induced anxiety-like behavior and dendritic spine elimination,promotes cortical spine formation,improves axonal myelination and enhance neuronal activity through BDNF/m TOR signal pathway,which provides a potential therapeutic target of the exercise training treatment for the neurological diseases.Moreover,we found potentiation of somatostatin interneuron activity sufficiently reverses the MPTP-induced dendritic spine dysfunction and neuronal/dendritic hyperactivity,which increased the cortical(sub)cellular evidences for the early-stage of PD treatment.